Metabolic profile, bioavailability and toxicokinetics of zearalenone-14-glucoside in rats after oral and intravenous administration by liquid chromatography high-resolution mass spectrometry and tandem mass spectrometry

Zearalenone-14-glucoside (ZEN-14G), a key modified mycotoxin, has attracted a great deal of attention due to the possible conversion to its free form of zearalenone (ZEN) exerting toxicity. In this study, the toxicokinetics of ZEN-14G were investigated in rats after oral and intravenous administration. The plasma concentrations of ZEN-14G and its major five metabolites were quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The data were analyzed via non-compartmental analysis using software WinNonlin 6.3. The results indicated that ZEN-14G was rapidly hydrolyzed into ZEN in vivo. In addition, the major parameters of ZEN-14G following intravenous administration were: area under the plasma concentration-time curve (AUC), 1.80 h.ng/mL; the apparent volume of distribution (V-Z), 7.25 L/kg; and total body clearance (CL), 5.02 mL/h/kg, respectively. After oral administration, the typical parameters were: AUC, 0.16 h.ng/mL; V-Z, 6.24 mL/kg; and CL, 4.50 mL/h/kg, respectively. The absolute oral bioavailability of ZEN-14G in rats was about 9%, since low levels of ZEN-14G were detected in plasma, which might be attributed to its extensive metabolism. Therefore, liquid chromatography high-resolution mass spectrometry (LC-HRMS) was adopted to clarify the metabolic profile of ZEN-14G in rats' plasma. As a result, eight metabolites were identified in which ZEN-14-glucuronic acid (ZEN-14GlcA) had a large yield from the first time-point and continued accumulating after oral administration, indicating that ZEN-14-glucuronic acid could serve a potential biomarker of ZEN-14G. The obtained outcomes would prompt the accurate safety evaluation of ZEN-14G

Mycotoxin exposure assessments in a multi-center European validation study by 24-hour dietary recall and biological fluid sampling

The European Food Consumption Validation (EFCOVAL) project includes 600 men and women from Belgium, the Czech Republic, France, the Netherlands, and Norway, who had given serum and 24-hour urine samples, and completed 24-hour dietary recall (24-HDR) interviews. Consumption, according to 24-HDR, was matched against the European Food Safety Authority (EFSA) databases of mycotoxin contaminations, via the FoodEx1 standard classifications, producing an indirect external estimate of dietary mycotoxin exposure. Direct, internal measurements of dietary mycotoxin exposure were made in serum and urine by ultra-performance liquid chromatography coupled to tandem mass spectrometry. For the first time, mycotoxin exposures were thoroughly compared between two 24-HDRs, and two 24-hour urine samples collected during the same days covered by the 24-HDRs. These measurements were compared to a single-time point serum measurement to investigate evidence of chronic mycotoxin exposure. According to 24-HDR data, all 600 individuals were exposed to between 4 and 34 mycotoxins, whereof 10 found to exceed the tolerable daily intake. Correlations were observed between two time points, and significant correlations were observed between concentrations in serum and urine. However, only acetyldeoxynivalenol, ochratoxin A, and sterigmatocystin were found to have significant positive correlations between 24-HDR exposures and serum, while aflatoxin G1 and G2, HT-2 toxin, and deoxynivalenol were associated between concurrent 24-HDR and 24-hour urine. Substantial agreements on quantitative levels between serum and urine were observed for the groups Type B Trichothecenes and Zearalenone. Further research is required to bridge the interpretation of external and internal exposure estimates of the individual on a time scale of hours. Additionally, metabolomic profiling of dietary mycotoxin exposures could help with a comprehensive assessment of single time-point exposures, but also with the identification of chronic exposure biomarkers. Such detailed characterization informs population exposure assessments, and aids in the interpretation of epidemiological health outcomes related to multi-mycotoxin exposure

Advancing Transformer Architecture in Long-Context Large Language Models: A Comprehensive Survey

Transformer-based Large Language Models (LLMs) have been applied in diverse areas such as knowledge bases, human interfaces, and dynamic agents, and marking a stride towards achieving Artificial General Intelligence (AGI). However, current LLMs are predominantly pretrained on short text snippets, which compromises their effectiveness in processing the long-context prompts that are frequently encountered in practical scenarios. This article offers a comprehensive survey of the recent advancement in Transformer-based LLM architectures aimed at enhancing the long-context capabilities of LLMs throughout the entire model lifecycle, from pre-training through to inference. We first delineate and analyze the problems of handling long-context input and output with the current Transformer-based models. We then provide a taxonomy and the landscape of upgrades on Transformer architecture to solve these problems. Afterwards, we provide an investigation on wildly used evaluation necessities tailored for long-context LLMs, including datasets, metrics, and baseline models, as well as optimization toolkits such as libraries, frameworks, and compilers to boost the efficacy of LLMs across different stages in runtime. Finally, we discuss the challenges and potential avenues for future research. A curated repository of relevant literature, continuously updated, is available at https://github.com/Strivin0311/long-llms-learning.Comment: 40 pages, 3 figures, 4 table

Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways

Stroke is the significant cause of human mortality and sufferings depending upon race and demographic location. Melatonin is a potent antioxidant that exerts protective effects in differential experimental stroke models. Several mechanisms have been previously suggested for the neuroprotective effects of melatonin in ischemic brain injury. The aim of this study is to investigate whether melatonin treatment affects the glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor signaling in cerebral cortex and striatum 24 h after permanent middle cerebral artery occlusion (MCAO). Melatonin (5 mg/kg) attenuated ischemia-induced down regulation of NMDA receptor 2 (NR2a), postsynaptic density-95 (PSD95) and increases NR2a/PSD95 complex association, which further activates the pro-survival PI3K/Akt/GSK3β pathway with mitigated collapsin response mediator protein 2 (CRMP2) phosphorylation. Furthermore, melatonin increases the expression of γ-enolase, a neurotrophic factor in ischemic cortex and striatum, and preserve the expression of presynaptic (synaptophysin and SNAP25) and postsynaptic (p-GluR1845) protein. Our study demonstrated a novel neuroprotective mechanism for melatonin in ischemic brain injury which could be a promising neuroprotective agent for the treatment of ischemic stroke

EUS assisted transmural cholecystogastrostomy fistula creation as a bridge for endoscopic internal gallbladder therapy using a novel fully covered metal stent

BACKGROUND: Laparoscopic cholecystectomy (LC) has become the “gold standard” for treating symptomatic gallstones. Innovative methods, such as a scarless therapeutic procedure through a natural orifice are being introduced, and include transgastric or transcolonic endoscopic cholecystectomy. However, before clinical implementation, instruments still need modification, and a more convenient treatment is still needed. The aim of this study was to evaluate the feasibility of endoscopic internal gallbladder therapy such as cholecystolithotomy in an animal survival model. METHODS: Four pigs underwent endoscopic-ultrasound (EUS)-guided cholecystogastrostomy and the placement of a novel covered mental stent. Four weeks later the stents were removed and an endoscope was advanced into the gallbladder via the fistula, and cholecystolithotomy was performed. Two weeks later the pigs were sacrificed, and the healing of the fistulas was assessed. RESULTS: EUS-guided cholecystogastrostomy with mental stent deployment was successfully performed in all the animals. Four weeks after the procedure, the fistulas had formed and all the stents were removed. Endoscopic cholecystolithotomy was performed through each fistula. All the animals survived until they were sacrificed 2 weeks later. The fistulas were found to be completely healed. CONCLUSIONS: This study reports the first endoscopic transmural cholecystolithotomy after placement of a novel mental stent in an animal survival model

Occurrence of neonicotinoids in Chinese apiculture and a corresponding risk exposure assessment

Neonicotinoids are the most widely used insecticides worldwide, but there is mounting evidence demonstrating that they have adverse effects on nontarget organisms. However, little is known about the extent of environmental neonicotinoids contamination in China. In this study, a total of 693 honey samples from across China, from both Apis melifera and Apis cerana, were analyzed to examine neonicotinoid concentrations and their geographical distribution, and correlation with the primary plant species from which the honey was obtained. Furthermore, chronic and acute exposure risk and risk ranking for humans eating honey were investigated, and risks to bees were also considered. The results revealed that 40.8% of the samples contained at least one of the five neonicotinoids tested. Honeys from commercial crops were found to be more frequently contaminated with neonicotinoids than those from noncommercial crops. Honey samples from Apis mellifera were more frequently contaminated than those from Apis cerana. The concentrations of neonicotinoids found in honey overlapped with those that have been found to have significant adverse effects on honeybee health. The dietary risk assessments indicated that the levels of neonicotinoids detected in honey were likely to be safe for human consumption